Hydrogenation process for the formation of 3,5-dihydro HMG-CoA reductase inhibitors

ABSTRACT

A novel hydrogenation process, using a homogenous iridium or rhodium catalyst for selectively adding hydrogen to the 3,5 positions in the polyhydronaphthyl ring of lovastatin, simvastatin or C-8-acyl or C-6-substituted analogs thereof, is disclosed.

BACKGROUND OF THE INVENTION

Mevinolin, also known as Lovastatin is a potent HMG-CoA reductase inhibitor and as such is an effective antihypercholesterolemic agent. Patchett et al. (U.S. Pat. No. 4,351,844) have found that a 3,5-dihydrolovastatin (I) is also a potent HMG-CoA reductase inhibitor. ##STR1## Patchett, et al., supra, describe a catalytic hydrogenation process, employing palladium on calcium carbonate in absolute ethanol, for the reduction of lovastatin to a compound of structure (I). This process has also been described by Kuo et al. J. Org. Chem, 48, 1991(1983). This palladium catalyzed hydrogenation has been described as yielding the 3,5 dihydrolovastatin together with varying amounts of the 3,4-dihydro isomer as a contaminant. Kuo et al, supra, also describe an alternative procedure for the synthesis of compound I vis-vis the treatment of tertbutyldimethylsilyl-lovastatin with triethyl silane in methylene chloride followed by protolysis with trifluoroacetic acid. However, this process requires silylation-desilylation and results in low yields of the desired 3,5-dihydro reduction product.

DETAILED DESCRIPTION OF THE INVENTION

The novel process of this invention may be depicted as: ##STR2## wherein: R₁ is H or C₁₋₃ alkyl;

R₂ is H or C₁₋₃ alkyl;

R₃ is C₁₋₅ alkyl, phenyl, or C₃₋₇ cycloalkyl; or C₁₋₅ alkyl or phenyl substituted with a group Y where Y is a group not reduced by the catalyst herein, examples of such a group Y are:

(a) t-C₄ H₉ (Me)₂ SiO--;

(b) halogen (F, Cl or Br);

(c) trifluoromethyl;

(d) C₁₋₃ alkoxy;

(e) C₁₋₃ alkylcarbonyloxy;

(f) phenylcarbonyloxy;

(g) C₁₋₃ alkoxycarbonyl; or

(h) phenyloxycarbonyl.

R₄ is H or CH₃ or CH₂ OSi(Me)₂ t-C₄ H₉ or OSi(Me)₂ t-C₄ H₉ ;

R₅ is H or CH₂ OSi(Me)₂ t-C₄ H₉ or OSi(Me)₂ t-C₄ H₉ ; provided that when either R₄ or R₅ is CH₂ OSi(Me)₂ t-C₄ H₉ the other is H; and one and only one of R₄ and R₅ can be OSi(Me)₂ t-C₄ H₉.

Alternatively R₄ and R₅ may be represented as:

R₄ is H or CH₃ or CH₂ OSi(Me)₂ t-C₄ H₉ ;

R₅ is H or CH₂ OSi(Me)₂ t-C₄ H₉ ;

provided that at least one of R₄ or R₅ is H.

Catalyst is [Ir(COD)PCy₃ (pyr)]PF₆ or [Rh(NBD)(DIPHOS-4)]BF₄ ; and

Solvent is dichloromethane, chloroform, chlorobenzene or a like substance;

Tert-butyldimethylsilyl is shown as a hydroxyl protecting group, it will be clear to those skilled in the art that other hydroxyl protecting groups such as tert-butyldiphenylsilyl trimethylsilyl, triethylsilyl, triisopropylsilyl and tetrahydropyranyl could be substituted for tert-butyldimethylsilyl without effecting the outcome of the instant invention.

The instant process selectively adds hydrogen to the 3,5 positions in the polyhydronaphthyl ring of lovastatin, simvastatin or C-8 acyl or C-6 substituted analogs thereof. A homogenous iridium or rhodium catalyst as described herein, is, in the absence of a hydroxyl coordination site at the C-8 position, able to distinguish between a 1,2 and a 1,4 hydrogenation, allowing only the 1,4 reduction under the herein described conditions. The 3,5-dihydro-product is formed in high yield uncontaminated by any other dihydro isomer.

One embodiment of the present invention is the preparation of compounds of structure (III) wherein:

R₁ is methyl,

R₂ is H or C₁₋₃ alkyl,

R₃ is C₁₋₅ alkyl, phenyl, or C₃₋₇ cycloalkyl; or C₁₋₅ alkyl or phenyl substituted with a group Y where Y is a group not reduced by the catalyst such as

(a) t-C₄ H₉ (Me)₂ SiO--;

(b) halogen (F, Cl or Br);

(c) trifluoromethyl;

(d) C₁₋₃ alkoxy;

(e) C₁₋₃ alkylcarbonyloxy;

(f) phenylcarbonyloxy;

(g) C₁₋₃ alkoxycarbonyl;

(h) phenyloxycarbonyl.

R₄ is CH₃ ; and

R₅ is H.

In one class of this embodiment, R₃ is C₁₋₅ alkyl

In a subclass are compounds (III) wherein:

a. R₂ is H and R₃ is CH₃ CH₂.

b. R₂ is CH₃ and R₃ is CH₃ CH₂.

A second embodiment is the preparation of compounds of structure (III) wherein:

R₁ is methyl,

R₂ is H or C₁₋₃ alkyl,

R₃ is C₁₋₅ alkyl, phenyl, or C₃₋₇ cycloalkyl; or C₁₋₅ alkyl or phenyl substituted with a group Y where Y is a group not reduced by the catalyst such as

(a) t-C₄ H₉ (Me)₂ SiO--;

(b) halogen (F, Cl or Br);

(c) trifluoromethyl;

(d) C₁₋₃ alkoxy;

(e) C₁₋₃ alkylcarbonyloxy

(f) phenylcarbonyloxy;

(g) C₁₋₃ alkoxycarbonyl;

(h) phenyloxycarbonyl.

R₄ is H or CH₂ OSi(Me)₂ t-C₄ H₉ ;

R₅ is H or CH₂ OSi(Me)₂ t-C₄ H₉ ; provided that at least one of R₄ and R₅ is H.

In one class of this embodiment, R₂ is H or CH₃, and R₃ is CH₃ CH₂.

In a subclass are compounds (III) wherein:

a. R₂ is H, R₄ is CH₂ OSi(Me)₂ t--C₄ H₉, R₅ is H.

b. R₂ is H, R₄ is H, R₅ is CH₂ OSi(Me)₂ t-C₄ H₉.

c. R₂ is CH₃, R₄ is CH₂ OSi(Me)₂ t-C₄ H₉, R₅ is H.

d. R₂ is CH₃, R₄ is H; R₅ is CH₂ OSi(Me)₂ t-C₄ H₉.

A third embodiment is the preparation of compounds of structure (III) wherein:

R₁ is methyl,

R₂ is H or C₁₋₃ alkyl,

R₃ is C₁₋₅ alkyl, phenyl, or C₃₋₇ cycloalkyl; or C₁₋₅ alkyl or phenyl substituted with a group Y where Y is a group not reduced by the catalyst such as

(a) t-C₄ H₉ (Me)₂ SiO--;

(b) halogen (F, Cl or Br);

(c) trifluoromethyl;

(d) C₁₋₃ alkoxy;

(e) C₁₋₃ alkylcarbonyloxy

(f) phenylcarbonyloxy;

(g) C₁₋₃ alkoxycarbonyl;

(h) phenyloxycarbonyl.

R₄ is H or CH₃ or OSi(Me)₂ t-C₄ H₉ ;

R₅ is H or OSi(Me)₂ t-C₄ H₉ ; provided that one and only one of R₄ and R₅ is OSi(Me)₂ t-C₄ H₉.

In one class of this embodiment, R₂ is H or CH₃, and R₃ is CH₃ CH₂.

In a subclass are compounds (III) wherein:

a. R₂ is H, R₄ is OSi(Me)₂ t-C₄ H₉ and R₅ is H;

b. R₂ is CH₃, R₄ is OSi(Me)₂ t-C₄ H₉ and R₅ is H;

c. R₂ is CH₃, R₄ is OSi(Me)₂ t-C₄ H₉ and R₅ is CH₃ ;

d. R₂ is H, R₄ is H and R₅ is OSi(Me)₂ t-C₄ H₉ ;

e. R₂ is H, R₄ is CH₃ and R₅ is OSi(Me)₂ t-C₄ H₉ ;

f. R₂ is CH₃, R₄ is H and R₅ is OSi(Me)₂ t-C₄ H₉ ;

g. R₂ is CH₃, R₄ is CH₃ and R₅ is OSi(Me)₂ t-C₄ H₉.

Starting diene, lovastatin, wherein R₁ is methyl, R₂ is hydrogen, R₃ is ethyl, R₄ is methyl and R₅ is hydrogen is readily available or may be prepared according to the fermentation procedures disclosed in U.S. Pat. No. 4,231,938. Simvastatin, wherein R₁ is methyl, R₂ is methyl, R₃ is ethyl, R₄ is methyl and R₅ is hydrogen may be prepared from lovastatin following the procedure described in U.S. Pat. No. 4,582,915 or copending U.S. application Ser. No. 072066 filed July 10, 1987. Starting dienes wherein R₄ or R₅ is CH₂ OSi(Me)₂ t-C₄ H₉ are prepared following the procedure outlined in copending U.S. Patent application Ser. No. 048136 filed May 15, 1987, followed by protection with t-C₄ H₉ (Me)₂ SiCl. Dienes where both R₄ and R₅ are hydrogen may be prepared from the fermentation product compactin (also known as mevastatin) (Endo, et al, J. Antibiot., 29, 1346 (1976)).

Compounds wherein R₄ or R₅ is OSi(Me)₂ t-C₄ H₉ can be prepared following the descriptions in U.S. Pat. Nos. 4,517,373 and 4,537,859 for preparing the C-6-hydroxyl derivatives followed by protection with t-C₄ H₉ (Me)₂ SiCl.

Dienes with substituted acyl groups are synthesized using acyl chlorides, prepared by standard techniques, and the acylation procedure described by Hoffman et al., in U.S. Pat. No. 4,444,784 or that disclosed in copending U.S. patent application Ser. No. 038580 filed Apr. 15, 1987.

The catalyst is [Ir(COD)PCy₃ (pyr)]PF₆ (COD=1,5-cyclooctadiene, PCy₃ =tricyclohexylphosphine, pyr=pyridine) or [Rh(NBD)(DIPHOS-4)]BF₄. (NBD=norbornadiene, DIPHOS-4=1,4 bis(diphenylphosphino)butane), preferably [Ir(COD)PCy₃ (pyr)]PF₆. The iridium catalyst may be prepared following the procedure described by Crabtree et al., J. Organomet. Chem., 135, 395 (1977). The rhodium catalyst can be prepared by the procedure outlined by Stille et al., J. Org. Chem., 47, 468 (1982), and supplemented by Evans et al., J. Am. Chem. Soc., 106, 3866 (1984).

The diene substrate and the iridium or rhodium catalyst in a mole percent of 0.1 to 10 mole percent catalyst to diene, preferably 2.5 mole percent catalyst to diene, is dissolved in dichloromethane, chloroform, chlorobenzene or a like solvent, preferably dichloromethane. The solution is reduced under atmospheric hydrogen pressure at a temperature of 25° to 80° C., preferably 25° C. After standard workup procedures, evaporation of solvent yields the desired 3,5 dihydro derivative.

The following Examples illustrate the present invention and as such are not to be considered as limiting the invention set forth in the claims appended hereto.

EXAMPLE 1 Preparation of 6(R) [2 [8(S) (2-methylbutyryloxy)-2(S),6(R)-dimethyl 1,2,3,5,6,7,8,8a(S)-octahydro-1(S)]ethyl]4(R) hydroxy -3,4,5,6 -tetrahydro -2H -pyran-2-one

A solution of lovastatin (0.63 g, 1.56 mmole) in dichloromethane (15 ml) was purged with argon gas. 1,5-Cyclooctadiene(pyridine)(tricyclohexylphosphine)iridium(I) hexafluorophosphate (0.0313 g, 2.5 mole percent) was added and the solution reduced at ambient temperature under one atmosphere hydrogen pressure. H₂ uptake was very rapid in the first 50 minutes. After 1 hour and 37 minutes, the reaction was stopped and the solution evaporated in vacuo to a yellow oil which was taken up in diethyl ether (50 ml) and filtered through a one inch bed of Florisil® (Magnesium silicate filter aid used herein to retain any catalyst complex which remained in solution). The filtrate was evaporated to give the title compound as a pale yellow oil. ¹ HNMR (300 MHz, CDCl₃) δ 5.48 (brs, 1H), 5.28 (m, 1H) 4.63 (m, 1H), 4.35 (m, 1H), 2.74 (dd, J=16,7Hz, 1H), 2.61 (dd, J=16, 4Hz, 1H), 1.22-2.45(m), 1.12 (d, J=7Hz, 3H), 1.0 (d, J=7Hz, 3H), 0.87 (t, J=7Hz, 3H), 0.82 (d, J=7Hz, 3H).

EXAMPLES 2-12

Following the procedure substantially as described in Example 1 but substituting for the mevinolin used as starting material therein, approximately equimolar amounts of structure (II) as described below there are prepared the corresponding 3,5-dihydro derivatives of structure (III).

    __________________________________________________________________________     R.sub.1  R.sub.2                                                                           R.sub.3                                                                             R.sub.4    R.sub.5                                            __________________________________________________________________________     Example 2                                                                            CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3 CH.sub.2                                                                   CH.sub.3   H                                                  Example 3                                                                            CH.sub.3                                                                          H  CH.sub.3 CH.sub.2                                                                   CH.sub.2 OSi(Me).sub.2 t-C.sub.4 H.sub.9                                                  H                                                  Example 4                                                                            CH.sub.3                                                                          H  CH.sub.3 CH.sub.2                                                                   H          CH.sub.2 OSi(Me).sub.2 t-C.sub.4 H.sub.9           Example 5                                                                            CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3 CH.sub.2                                                                   CH.sub.2 OSi(Me).sub.2 t-C.sub.4 H.sub.9                                                  H                                                  Example 6                                                                            CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3 CH.sub.2                                                                   H          CH.sub.2 OSi(Me).sub.2 t-C.sub.4 H.sub.9           Example 7                                                                            CH.sub.3                                                                          H  CH.sub.3 CH.sub.2                                                                   CH.sub.2 OSi(Me).sub.2 t-C.sub.4 H.sub.9                                                  H                                                  Example 8                                                                            CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3 CH.sub.2                                                                   CH.sub.2 OSi(Me).sub.2 t-C.sub.4 H.sub.9                                                  H                                                  Example 9                                                                            CH.sub.3                                                                          H  CH.sub.3 CH.sub.2                                                                   H          CH.sub.2 OSi(Me).sub.2 t-C.sub.4 H.sub.9           Example 10                                                                           CH.sub.3                                                                          H  CH.sub.3 CH.sub.2                                                                   CH.sub.3   CH.sub.2 OSi(Me).sub.2 t-C.sub.4 H.sub.9           Example 11                                                                           CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3 CH.sub.2                                                                   H          CH.sub.2 OSi(Me).sub.2 t-C.sub.4 H.sub.9           Example 12                                                                           CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3 CH.sub.2                                                                   CH.sub.3   CH.sub.2 OSi(Me).sub.2 t-C.sub.4 H.sub.9           __________________________________________________________________________ 

What is claimed is:
 1. A process for the preparation of a compound of structural formula (III): ##STR3## wherein: R₁ is H or C₁₋₃ alkyl;R₂ is H or C₁₋₃ alkyl; R₃ is C₁₋₅ alkyl, phenyl, or C₃₋₇ cycloalkyl; or C₁₋₅ alkyl or phenyl substituted with a group Y where Y is selected from the group consisting of:(a) t-C₄ H₉ (Me)₂ SiO--, (b) halogen, (c) trifluoromethyl, (d) C₁₋₃ alkoxy, (e) C₁₋₃ alkylcarbonyloxy, (f) phenylcarbonyloxy, (g) C₁₋₃ alkoxycarbonyl, (h) phenyloxycarbonyl; R₄ is H or CH₃ or CH₂ OSi(Me)₂ t-C₄ H₉ or OSi(Me)₂ t-C₄ H₉ ; R₅ is H, or CH₂ OSi(Me)₂ t-C₄ H₉ or OSi(Me)₂ t-C₄ H₉ ; provided that when either R₄ or R₅ is CH₂ OSi(Me)₂ t-C₄ H₉ the other is H; and one and only one of R₄ and R₅ can be OSi(Me)₂ t-C₄ H₉.which comprises: contacting a compound of structural formula (II) ##STR4## with 1,5-cyclooctadiene(pyridine)(tricyclohexylphosphine)iridium(I) hexafluorophosphate or norbornadiene-1,4-bis(diphenylphosphino)butanerhodium(I) tetrafluoroborate in a solvent, under an atmospheric pressure of hydrogen gas at 25° to 80° C.
 2. A process of claim 1 wherein:R₄ is H or CH₃ or CH₂ OSi(Me)₂ t-C₄ H₉ ; R₅ is H or CH₂ OSi(Me)₂ t-C₄ H₉ ; provided that when either R₄ or R₅ is CH₂ OSi(Me)₂ t-C₄ H₉ the other is H.
 3. A process of claim 1 wherein the catalyst is 1,5-cyclooctadiene(pyridine)(tricyclohexylphosphine)iridium(I) hexafluorophosphate.
 4. A process of claim 3 wherein the solvent is selected from dichloromethane, chloroform or chlorobenzene.
 5. A process of claim 4 wherein the temperature is about 25° C., and the solvent is dichloromethane.
 6. A process of claim 5 wherein the mole percent of catalyst to diene is about 2.5 mole percent.
 7. A process of claim 1 wherein:R₁ is CH₃, R₄ is CH₃ ; and R₅ is H.
 8. A process of claim 7 wherein:R₃ is C₁₋₅ alkyl.
 9. A process of claim 8 wherein the compound (III) prepared is selected from the group wherein:a. R₂ is H and R₃ is CH₃ CH₂ ; b. R₂ is CH₃ and R₃ is CH₃ CH₂.
 10. A process of claim 1 wherein:R₁ is CH₃, R₄ is H or CH₂ OSi(Me)₂ t-C₄ H₉ ; R₅ is H or CH₂ OSi(Me)₂ t-C₄ H₉ ; provided that at least one of R₄ or R₅ is H.
 11. A process of claim 10 wherein:R₂ is H or CH₃ ; and R₃ is CH₃ CH₂.
 12. A process of claim 11 wherein the compound (III) prepared is selected from the group wherein:a. R₂ is H, R₄ is CH₂ OSi(Me)₂ t-C₄ H₉ and R₅ is H; b. R₂ is H, R₄ is H and R₅ is CH₂ OSi(Me)₂ t-C₄ H₉ ; c. R₂ is CH₃, R₄ is CH₂ OSi(Me)₂ t-C₄ H₉ and R₅ is H; d. R₂ is CH₃, R₄ is H and R₅ is CH₂ OSi(Me)₂ t-C₄ H₉.
 13. A process of claim 1 wherein:R₁ is CH₃, R₄ is H or CH₃ or OSi(Me)₂ t-C₄ H₉ ; R₅ is H or OSi(Me)₂ t-C₄ H₉ ; provided that one and only one of R₁ and R₂ is OSi(Me)₂ t-C₄ H₉.
 14. A process of claim 13 wherein:R₂ is H or CH₃ ; and R₃ is CH₃ CH₂.
 15. A process of claim 14 wherein the compound (III) prepared is selected form the group wherein:a. R₂ is H, R₄ is OSi(Me)₂ t-C₄ H₉ and R₅ is H; b. R₂ is CH₃, R₄ is OSi(Me)₂ t-C₄ H₉ and R₅ is H; c. R₂ is H, R₄ is H and R₅ is OSi(Me)₂ t-C₄ H₉ ; d. R₂ is H, R₄ is CH₃ and R₅ is OSi(Me)₂ t-C₄ H₉ ; e. R₂ is CH₃, R₄ is H and R₅ is OSi(Me)₂ t-C₄ H₉ ; f. R₂ is CH₃, R₄ is CH₃ and R₅ is OSi(Me)₂ t-C₄ H₉.
 16. A process of claim 9 wherein the catalyst is 1,5 cyclooctadiene(pyridine)(tricyclohexylphosphine)iridium(I) hexafluorophosphate, the solvent is dichloromethane, the temperature is about 25° C. and the mole percent catalyst to diene is 2.5 mole percent.
 17. A process of claim 12 wherein the catalyst is 1,5 cyclooctadiene(pyridine)(tricyclohexylphosphine)iridium(I) hexafluorophosphate, the solvent is dichloromethane, the temperature is about 25° C. and the mole percent catalyst to diene is 2.5 mole percent.
 18. A process of claim 15 wherein the catalyst is 1,5-cyclooctadiene(pyridine)(tricyclohexylphosphine)iridium(I) hexafluorophosphate, the solvent is dichloromethane, the temperature is about 25° C. and the mole percent catalyst to diene is 2.5 mole percent. 